PROJECT SUMMARY/ABSTRACT ? CANCER IMMUNOLOGY (CI) PROGRAM The Cancer Immunology (CI) Program of The Tisch Cancer Institute (TCI) is comprised of 30 members who share a common goal to investigate the premise that immune-mediated dysregulation adversely impacts the TME. They represent 15 Departments and 7 Institutes. As of February 2019, CI program members were awarded $8.8 million in direct cost funding, with NCI support of $2.5 million and peer-reviewed cancer related support of $5 million. In 2018, the program published 72 papers of which 30% were intra- and 18% were inter- programmatic. The major scientific themes of the CI program are to investigate: 1. Immune dysregulation in the Tumor Microenvironment (TME); 2. Develop models to reverse immune dysfunction and restore immune balance; and 3. Validate correlates of response in cancer patients receiving immunotherapy. Cancer progression is characterized by gradual dysregulation of the immune system at multiple levels that directly contributes to unchecked tumor growth. While the role of T cell dysfunction is well acknowledged, evidence is accumulating that the innate immune system is analogously hijacked to enable tumor growth. In this regard, CI Program members are focused on identifying new mechanisms whereby the tumor microenvironment (TME) impacts the function of innate immune cells including macrophages, dendritic cells and NK cells, in addition to tumor-reactive T cells. Accordingly, the CI program has three main scientific goals. The first is to identify genomic, molecular and cellular pathways underlying immune dysfunction in the TME. CI members use preclinical model systems, CRISPR screens and human tumor lesions, to identify novel mechanisms/targets underlying immune dysregulation and prioritize targets of immunotherapy resistance/response ultimately tested in novel clinical trials. Second, CI members strive to develop scientifically based strategies that will improve and/or expand current immunotherapeutic platforms, and identify immune biomarkers of risk and response to treatment. The overarching goal is to progress discoveries that are made into innovative clinical trials to test and validate proposed correlates of resistance and response. A third goal is to develop novel clinically applicable immune targets to effectively control or eradicate cancers. CI members work in partnership and inter-programmatically to validate correlates of resistance to immunotherapy.